The overarching goal of this study is to understand the molecular mechanisms underpinning bacterial collective behaviors required for causing acute gastric infections in humans. To explore this, quorum sensing, the process of cell-cell communication in the pathogenic bacterium Vibrio cholerae will be studied. V. cholerae is the etiological agent of the disease cholera, a severe diarrheal condition that is a source of enormous public health concern in the developing world. Quorum sensing in V. cholerae depends on the production, release, detection, and response to extracellular signaling molecules called autoinducers. Group-wide detection of autoinducers allows V. cholerae to synchronously alter its behavior in response to changes in the population density and species composition of the vicinal bacterial community. In V. cholerae, quorum sensing is activated by two autoinducers, CAI-1 and AI-2. CAI-1, the dominant signal, is detected by the membrane-bound histidine sensor kinase, CqsS, and these are the focus of this study. In V. cholerae, quorum sensing represses biofilm formation and virulence factor production. Thus, molecules that activate quorum sensing (pro-quorum sensing molecules) have the potential to repress virulence in V. cholerae and to be developed into therapeutics. The goal of this study is to define the molecular mechanism by which specific molecules are recognized by the CqsS receptor and determine how they elicit the quorum sensing response. Particularly interesting are ligand- receptor interactions between CqsS and the recently discovered CqsS agonist called WYZ301. WYZ301 is structurally distinct from CAI-1 and yet it potently agonizes quorum sensing. Studying new molecules, such as WYZ301, should greatly enhance the understanding of how CqsS interacts with ligands to generate the quorum sensing response. More generally, these studies will contribute to the development of novel therapeutics for V. cholerae, closely related pathogenic vibrios, as well as other diarrhea-causing bacteria that use quorum sensing for collective behaviors, including virulence.